Novel Curcumin Inspired Bis-Chalcone Promotes Endoplasmic Reticulum Stress and Glioblastoma Neurosphere Cell Death
Glioblastoma (GBM) has a dismal prognosis and successful elimination of GBM stem cells (GSCs) is a high-priority as these cells are responsible for tumor regrowth following therapy and ultimately patient relapse. Natural products and their derivatives continue to be a source for the development of e...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-03-01
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| Series: | Cancers |
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| Online Access: | http://www.mdpi.com/2072-6694/11/3/357 |
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| author | Lorenzo Sansalone Eduardo A. Veliz Nadia G. Myrthil Vasileios Stathias Winston Walters Ingrid I. Torrens Stephan C. Schürer Steven Vanni Roger M. Leblanc Regina M. Graham |
| author_facet | Lorenzo Sansalone Eduardo A. Veliz Nadia G. Myrthil Vasileios Stathias Winston Walters Ingrid I. Torrens Stephan C. Schürer Steven Vanni Roger M. Leblanc Regina M. Graham |
| author_sort | Lorenzo Sansalone |
| collection | DOAJ |
| description | Glioblastoma (GBM) has a dismal prognosis and successful elimination of GBM stem cells (GSCs) is a high-priority as these cells are responsible for tumor regrowth following therapy and ultimately patient relapse. Natural products and their derivatives continue to be a source for the development of effective anticancer drugs and have been shown to effectively target pathways necessary for cancer stem cell self-renewal and proliferation. We generated a series of curcumin inspired bis-chalcones and examined their effect in multiple patient-derived GSC lines. Of the 19 compounds synthesized, four analogs robustly induced GSC death in six separate GSC lines, with a half maximal inhibitory concentration (IC50) ranging from 2.7–5.8 μM and significantly reduced GSC neurosphere formation at sub-cytotoxic levels. Structural analysis indicated that the presence of a methoxy group at position 3 of the lateral phenylic appendages was important for activity. Pathway and drug connectivity analysis of gene expression changes in response to treatment with the most active bis-chalcone 4j (the 3,4,5 trimethoxy substituted analog) suggested that the mechanism of action was the induction of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) mediated cell death. This was confirmed by Western blot analysis in which 4j induced robust increases in CHOP, p-jun and caspase 12. The UPR is believed to play a significant role in GBM pathogenesis and resistance to therapy and as such represents a promising therapeutic target. |
| first_indexed | 2024-03-12T10:18:10Z |
| format | Article |
| id | doaj.art-e0312d8fd371450c96f08a567091009f |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T10:18:10Z |
| publishDate | 2019-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-e0312d8fd371450c96f08a567091009f2023-09-02T10:22:09ZengMDPI AGCancers2072-66942019-03-0111335710.3390/cancers11030357cancers11030357Novel Curcumin Inspired Bis-Chalcone Promotes Endoplasmic Reticulum Stress and Glioblastoma Neurosphere Cell DeathLorenzo Sansalone0Eduardo A. Veliz1Nadia G. Myrthil2Vasileios Stathias3Winston Walters4Ingrid I. Torrens5Stephan C. Schürer6Steven Vanni7Roger M. Leblanc8Regina M. Graham9Department of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables, FL 33146, USADepartment of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables, FL 33146, USAUniversity of Miami Brain Tumor Initiative, Department of Neurosurgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USAUniversity of Miami Brain Tumor Initiative, Department of Neurosurgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USAUniversity of Miami Brain Tumor Initiative, Department of Neurosurgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USAUniversity of Miami Brain Tumor Initiative, Department of Neurosurgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USASylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1475 NW 12th Ave, Miami, FL 33136, USADepartment of Neurosurgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USADepartment of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables, FL 33146, USAUniversity of Miami Brain Tumor Initiative, Department of Neurosurgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USAGlioblastoma (GBM) has a dismal prognosis and successful elimination of GBM stem cells (GSCs) is a high-priority as these cells are responsible for tumor regrowth following therapy and ultimately patient relapse. Natural products and their derivatives continue to be a source for the development of effective anticancer drugs and have been shown to effectively target pathways necessary for cancer stem cell self-renewal and proliferation. We generated a series of curcumin inspired bis-chalcones and examined their effect in multiple patient-derived GSC lines. Of the 19 compounds synthesized, four analogs robustly induced GSC death in six separate GSC lines, with a half maximal inhibitory concentration (IC50) ranging from 2.7–5.8 μM and significantly reduced GSC neurosphere formation at sub-cytotoxic levels. Structural analysis indicated that the presence of a methoxy group at position 3 of the lateral phenylic appendages was important for activity. Pathway and drug connectivity analysis of gene expression changes in response to treatment with the most active bis-chalcone 4j (the 3,4,5 trimethoxy substituted analog) suggested that the mechanism of action was the induction of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) mediated cell death. This was confirmed by Western blot analysis in which 4j induced robust increases in CHOP, p-jun and caspase 12. The UPR is believed to play a significant role in GBM pathogenesis and resistance to therapy and as such represents a promising therapeutic target.http://www.mdpi.com/2072-6694/11/3/357cancer stem cellendoplasmic reticulum stressglioblastoma multiformeunfolded protein responsecurcuminbis-chalconesbrain tumorglioblastoma stem cell |
| spellingShingle | Lorenzo Sansalone Eduardo A. Veliz Nadia G. Myrthil Vasileios Stathias Winston Walters Ingrid I. Torrens Stephan C. Schürer Steven Vanni Roger M. Leblanc Regina M. Graham Novel Curcumin Inspired Bis-Chalcone Promotes Endoplasmic Reticulum Stress and Glioblastoma Neurosphere Cell Death Cancers cancer stem cell endoplasmic reticulum stress glioblastoma multiforme unfolded protein response curcumin bis-chalcones brain tumor glioblastoma stem cell |
| title | Novel Curcumin Inspired Bis-Chalcone Promotes Endoplasmic Reticulum Stress and Glioblastoma Neurosphere Cell Death |
| title_full | Novel Curcumin Inspired Bis-Chalcone Promotes Endoplasmic Reticulum Stress and Glioblastoma Neurosphere Cell Death |
| title_fullStr | Novel Curcumin Inspired Bis-Chalcone Promotes Endoplasmic Reticulum Stress and Glioblastoma Neurosphere Cell Death |
| title_full_unstemmed | Novel Curcumin Inspired Bis-Chalcone Promotes Endoplasmic Reticulum Stress and Glioblastoma Neurosphere Cell Death |
| title_short | Novel Curcumin Inspired Bis-Chalcone Promotes Endoplasmic Reticulum Stress and Glioblastoma Neurosphere Cell Death |
| title_sort | novel curcumin inspired bis chalcone promotes endoplasmic reticulum stress and glioblastoma neurosphere cell death |
| topic | cancer stem cell endoplasmic reticulum stress glioblastoma multiforme unfolded protein response curcumin bis-chalcones brain tumor glioblastoma stem cell |
| url | http://www.mdpi.com/2072-6694/11/3/357 |
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